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CTRI Number  CTRI/2018/04/013474 [Registered on: 25/04/2018] Trial Registered Prospectively
Last Modified On: 06/05/2021
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   The Effect of Vitamin C on Post-Operative opioid Requirement in orthopaedic lower limb surgery 
Scientific Title of Study   The Effect of Ascorbic Acid on Post-Operative opioid Requirement in orthopaedic lower limb surgery 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Lingaraj Sahu 
Designation  Asst Professor 
Affiliation  KIMS 
Address  Dept. of Anaesthesiology KIMS, Bhubaneswar KHORDA ODISSA
202, Trishna Orchid, Kanan Vihar II, Bhubaneswar 751031
Khordha
ORISSA
751024
India 
Phone  8280166501  
Fax    
Email  drlingarajsahu.2008@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Lingaraj Sahu 
Designation  Asst Professor 
Affiliation  KIMS 
Address  Dept. of Anaesthesiology KIMS, Bhubaneswar KHORDA ODISSA
202, Trishna Orchid, Kanan Vihar II, Bhubaneswar 751031

ORISSA
751024
India 
Phone  8280166501  
Fax    
Email  drlingarajsahu.2008@gmail.com  
 
Details of Contact Person
Public Query  
Name  Dr Lingaraj Sahu 
Designation  Asst Professor 
Affiliation  KIMS 
Address  Dept. of Anaesthesiology KIMS, Bhubaneswar KHORDA ODISSA
202, Trishna Orchid, Kanan Vihar II, Bhubaneswar 751031

ORISSA
751024
India 
Phone  8280166501  
Fax    
Email  drlingarajsahu.2008@gmail.com  
 
Source of Monetary or Material Support  
Kalinga institute of Medical Sciences, Patia, Bhubaneswar-24, Orissa 
 
Primary Sponsor  
Name  KIMS 
Address  KIMS, PATIA,BHUBANESWAR 
Type of Sponsor  Private medical college 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
DR LINGARAJ SAHU  Kalinga Institute of Medical Sciences  PATIA BHUBANESWAR 751024
Khordha
ORISSA 		 8280166501

drlingarajsahu.2008@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Institutional ethics committee, Kalinga Institute of Medical Sciences, Bhubaneswar  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  ASA I & II,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Ascorbic Acid  1.5gm of ascorbic acid will be given iv to the experimental group. the post operative opioid requirement will be studied between two groups 
Comparator Agent  nil  nil 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  60.00 Year(s)
Gender  Both 
Details  1. Willing patients 2. Age group 18-60years of either sex 3. ASA I & II
4. Lower limb orthopaedic surgery under sub arachnoid block
 
 
ExclusionCriteria 
Details  1. History of drug abuse 2. Any Suffering from Chronic pain 3. Allergic history to opioids or Ascorbic acid
4. Regular analgesic user or any analgesic taken within 12 hours before surgery. 5. History of renal calculi
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   An Open list of random numbers 
Blinding/Masking   Not Applicable 
Primary Outcome  
Outcome  TimePoints 
comparing requirement of opioids during first 24 hours of post-operative period with cotrol group  comparing requirement of opioids during first 24 hours of post-operative period with cotrol group 
 
Secondary Outcome  
Outcome  TimePoints 
any complications like allergy reaction to ascorbic acid, phlebitis, pain during infusion  24 hours 
 
Target Sample Size   Total Sample Size="110"
Sample Size from India="110" 
Final Enrollment numbers achieved (Total)= "110"
Final Enrollment numbers achieved (India)="110" 
Phase of Trial   N/A 
Date of First Enrollment (India)   30/04/2018 
Date of Study Completion (India) 13/06/2019 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="0"
Months="6"
Days="6" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   none 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary
Modification(s)  

The Effect of Ascorbic Acid on Post-Operative opioid Requirement in orthopaedic lower limb surgery

Dr Lingaraj Sahu, Asst Prof. dept. of Anaesthesiology

Dr Debashish Mishra, Asst Prof., Dept. of Orthopaedics

Dr Jagadish Chandra Mishra, Associate Prof, Dept. of Anaesthesiology

BACKGROUND

Ascorbic Acid (AA) is an antioxidant that serves as a cofactor for many enzymes, and plays a role in synthesis of collagen, neurotransmitter, and numerous neuropeptides. It exhibits anti-inflammatory properties, providing marked decreases in markers of inflammation such as C-reactive protein and pro-inflammatory cytokines, e.g. tumour necrosis factor, interferon and interleukins[1]. It has a potential role in the synthesis of amidated opioid peptides[2,3]. A number of amidated neuropeptides have potent opioid activity [4]. It acts as a cofactor for the enzyme dopamine β-hydroxylase which converts dopamine into norepinephrine [5,6]. AA recycles the cofactor tetrahydrobiopterin, which is required for optimal activity of the rate-limiting enzyme in the biosynthesis of monoamine neurotransmitter serotonin[7]. These two, norepinephrine and serotonin plays a role in decreasing pain [8].  

Trauma and surgery increases consumption of AA and hence significant deplete in vitamin C concentration [9].

Studies shows that ascorbic acid is effective in cancer related pain, virus related pain and complex regional pain syndrome (CRPS). Some studies also shows that it decreases post operative opioid requirement. The drawback of these studies are they used single large oral/intravenous dose of ascorbic acid on the day of surgery well before start of surgery.  Considering the pharmacokinetics of ascorbic acid, in the enteral route, uptake becomes less efficient as the dose increases due to saturation of the sodium-dependant vitamin C transporters (SVCT-1)[10]. The T1/2 of AA is (2 + 0.6) hours[11]. So the serum concentration of AA also falls rapidly. Giving AA in either route well before starting of the surgery will not maintain the serum concentration till the end of surgery or much in the post-operative period. So here we design the study keeping the pharmacokinetics in mind to study the effect of AA on post operative opioid requirement.

AIM: To study the effect of ascorbic acid on post operative opioid requirement.

Duration of study: 6 months

Sample size: By adopting the reported Standard deviation of 1.0 in placebo group and 0.8 in experimental group and the reduction of 0.6 unit of frequency of rescue analgesia in experimental group at 1% level of significance with minimum study power of 80%, the require sample size per group is 53. Accordingly a total of 110 subjects will be required for the current study.

Type of study:  

Randomised  controlled trial.

Inclusion Criteria:      1. Willing patients

                                    2. Age group 18-60years of either sex

                                    3. ASA I & II

                                    4. Lower limb orthopaedic surgery under sub  arachnoid block

 

Exclusion Criteria:     1. History of drug abuse

                                    2. Any Suffering from Chronic pain

                                    3. Allergic history to opioids or Ascorbic acid

                                    4. Regular analgesic user or any analgesic taken   within 12 hours before surgery.

                                    5. History of renal calculi

Materials and Methods:

Patients will be enrolled in the study after meeting inclusion and exclusion criteria. Written informed consent will be taken. Simple randomisation (list attached) has been done between two groups using the standard statistical software. Patients will be grouped into two, control and experimental with this randomisation list. Operation will be conducted under sub-arachnoid block (SAB) with 3ml of 0.5% bupivacaine heavy upto the T8 segment block. Paracetamol injection at a dose of 20 mg/kg will be given I.V. to each patient from both the groups after two hours and twelve hours after start of SAB. Two doses of 1.5 gm of Ascorbic Acid each will be diluted in 100 ml normal saline   will be infused intra-venously over 30 min duration to the experimental group after the paracetamol infusion.  After surgery they will be shifted to post anaesthetic care unit and subsequently to their respective wards.

 The pain (VAS) score at 2, 4, 6, 8,10,12,18 and 24 hours from start of SAB will be recorded by resident doctor. If VAS is of > 3 than 25 microgram incremental dose of fentanyl will be given i.v. at an interval of 5 minutes till pain score comes below three.

 

Data Collection and Analysis:

The VAS at the above mentioned time will be collected. The amount of fentanyl requirement at different time period and the total fentanyl requirement will be recorded. Any drug reaction or side effects will also be recorded.

Statistical Analysis

All the qualitative parameter will be represented as frequency and percentage whereas the continuous parameter will be reported as mean ± standard deviation. A ‘p’ value of <0.05 will be considered as statistically significant. All the statistical analysis will be carried out after the collection of data using standard statistical software Stata 13.1.

References:

1.    Mikirova N, Casciari J, Rogers A, Taylor P. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med. 2012;10:189. doi: 10.1186/1479-5876-10-189.[PMC free article] [PubMed] 

2.    Prigge ST, Mains RE, Eipper BA, Amzel LM. New insights into copper monooxygenases and peptide amidation: structure, mechanism and function. Cell Mol Life Sci. 2000;57(8–9):1236–1259. doi: 10.1007/PL00000763. [PubMed] 

3.    Merkler DJ. C-terminal amidated peptides: production by the in vitro enzymatic amidation of glycine-extended peptides and the importance of the amide to bioactivity. Enzyme Microb Technol. 1994;16(6):450–456. doi: 10.1016/0141-0229(94)90014-0. [PubMed] 

4.    Okada Y, Tsuda Y, Bryant SD, Lazarus LH. Endomorphins and related opioid peptides. Vitam Horm. 2002;65:257–279. doi: 10.1016/S0083-6729(02)65067-8. [PubMed] 

5.    Levine M. Ascorbic acid specifically enhances dopamine beta-monooxygenase activity in resting and stimulated chromaffin cells. J Biol Chem. 1986;261(16):7347–7356. [PubMed]

6.    May JM, Qu ZC, Nazarewicz R, Dikalov S. Ascorbic acid efficiently enhances neuronal synthesis of norepinephrine from dopamine. Brain Res Bull. 2013;90:35–42. doi: 10.1016/j.brainresbull.2012.09.009.[PMC free article] [PubMed]

7.     Ward MS, Lamb J, May JM, Harrison FE. Behavioral and monoamine changes following severe vitamin C deficiency. J Neurochem. 2013;124(3):363–375. doi: 10.1111/jnc.12069. [PMC free article][PubMed] 

8.     Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol. 2004;19(Suppl 1):S15–S19. doi: 10.1002/hup.620. [PubMed] 

 

9.    Fukushima R, Yamazaki E. Vitamin C requirement in surgical patients. Curr Opin Clin Nutr Metab Care. 2010;13(6):669–676. doi: 10.1097/MCO.0b013e32833e05bc. [PubMed] 

10. Savini I, Rossi A, Pierro C, Avigliano L, Catani MV. SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids. 2008;34(3):347–355. doi: 10.1007/s00726-007-0555-7. [PubMed] 

11.  Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013;72(1):139–146. doi: 10.1007/s00280-013-2179-9. [PMC free article][PubMed] 

 

 

 

 

 

 

 

 

 

 

 

 

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